Wang R, Wang Z, Wu L, Hanna S T, Peterson-Wakeman R
Department of Physiology, University of Saskatchewan, Saskatoon, Canada.
Diabetes. 2001 Jan;50(1):166-74. doi: 10.2337/diabetes.50.1.166.
Carbon monoxide (CO) is an endogenous gaseous factor that relaxes vascular tissues by acting on both the cGMP pathway and calcium-activated K+ (K(Ca)) channels. Whether the vascular effect of CO is altered in diabetes had been unknown. It was found that the CO-induced relaxation of tail artery tissues from streptozotocin-induced diabetic rats was significantly decreased as compared with that of nondiabetic control rats. The blockade of the cGMP pathway with ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one) completely abolished the CO-induced relaxation of diabetic tissues but only partially inhibited the CO effect in normal tissues. Single-channel conductance of K(Ca) channels in diabetic smooth muscle cells (SMCs) was not different from that of normal SMCs. However, the sensitivity of K(Ca) channels to CO in diabetic SMCs was significantly reduced. CO (10 micromol/l) induced an 81 +/- 24% increase in the mean open probability of single K(Ca) channels in normal SMCs but had no effect in diabetic SMCs. Longterm culture of normal vascular SMCs with 25 mmol/l glucose or 25 mmol/l 3-OMG (3-O-methylglucose) but not 25 mmol/l mannitol significantly reduced the sensitivity of K(Ca) channels to CO. On the other hand, the sensitivity of K(Ca) channels to CO was regained in diabetic SMCs that were cultured with 5 mmol/l glucose for a prolonged period. The decreased vasorelaxant effect of CO in diabetes represents a novel mechanism for the vascular complications of diabetes, which could be closely related to the glycation of K(Ca) channels in diabetic vascular SMCs.
一氧化碳（CO）是一种内源性气体因子，可通过作用于环鸟苷酸（cGMP）途径和钙激活钾离子（K（Ca））通道来舒张血管组织。糖尿病时CO的血管效应是否改变尚不清楚。研究发现，与非糖尿病对照大鼠相比，链脲佐菌素诱导的糖尿病大鼠尾动脉组织中CO诱导的舒张作用显著降低。用ODQ（1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮）阻断cGMP途径可完全消除糖尿病组织中CO诱导的舒张作用，但仅部分抑制正常组织中CO的作用。糖尿病平滑肌细胞（SMC）中K（Ca）通道的单通道电导与正常SMC无差异。然而，糖尿病SMC中K（Ca）通道对CO的敏感性显著降低。CO（10微摩尔/升）可使正常SMC中单个K（Ca）通道的平均开放概率增加81±24%，但对糖尿病SMC无影响。用25毫摩尔/升葡萄糖或25毫摩尔/升3-OMG（3-O-甲基葡萄糖）而非25毫摩尔/升甘露醇长期培养正常血管SMC可显著降低K（Ca）通道对CO的敏感性。另一方面，用5毫摩尔/升葡萄糖长期培养的糖尿病SMC中，K（Ca）通道对CO的敏感性得以恢复。糖尿病中CO血管舒张作用的降低代表了糖尿病血管并发症的一种新机制，这可能与糖尿病血管SMC中K（Ca）通道的糖基化密切相关。
